Methods of making low odor choline salts of an organic compound

ABSTRACT

Methods of making low odor choline salts of an organic compound, for example, choline ellagate compound(s), and uses and formulations thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 16/313,760filed on Dec. 27, 2018, which is a national phase application under 35U.S.C. § 371 of International Application No. PCT/IB2017/053943 filed onJun. 29, 2017, which claims the benefit of U.S. Provisional ApplicationNo. 62/356,311, filed on Jun. 29, 2016. The contents of the referencedapplications are incorporated into the present application by reference.

BACKGROUND OF THE INVENTION

A. Field of the Invention

The present invention relates to methods of making choline salt(s) of anorganic compound. In particular, the invention relates to methods ofmaking low odor choline salt(s) of an organic compound, such as cholineellagate compound(s).

B. Description of Related Art

Choline is a quaternary (2-hydroxyethyl-trimethyl) amine that playsimportant roles in mediating cell growth and cellular repair. Cholinecan assist in the mobilization of nutrients, including lipids, vitamincofactors, and amino acids. Choline is an important part of a balanceddiet and is considered an essential nutrient. Men, post-menopausalwomen, people on low calorie diets, and pregnant women can be at risk ofbecoming choline deficient, which can lead to plasma homocysteine,accumulation of fat in the liver, damage to the liver, lymphocytes,muscles, and even organ dysfunction.

Choline and water soluble choline salts are used in fortified foods anddietary supplements to assist in the delivery and uptake of nutrients,and to help provide the recommended daily intake of this essentialnutrient. By way of example, U.S. Pat. No. 3,576,007 to Hochstiendescribes methods of making dicholine ellagate from ellagic acid andcholine by reacting the choline with the ellagic acid dissolved indimethyl formamide at 100° C. In another example, Sintra et al.,describes making choline salts of ellagic acid by reacting a methanolichydroxide salt of choline and the ellagic acid at room temperature andforming the dicholine ellagate by removing the methanol under vacuum toleave the dicholine ellagate residue.

Despite the foregoing, many commercial preparations of dicholineellagate and other choline ellagate salts result in a compound that hasan amine (e.g., fish-like) odor, which can negatively affect consumeracceptance of these products

SUMMARY OF THE INVENTION

The present invention provides a solution to the current problems facingthe production of choline compositions and use of choline in foods,pharmaceuticals, and/or nutraceuticals. It was surprisingly found thatthe choline salt(s) of an organic compound disclosed herein have lessodor in comparison with choline and salts thereof, (e.g., dicholineellagate) made by conventional methods. Without wishing to be bound bytheory, it is believed that the odor of the choline salts can be theresult of (a) impurities in the commercial preparations from theproduction process of choline or choline salts or (b) degradation of thecholine or choline salts.

Thus, the choline salt(s) of an organic compound made by the methodsdisclosed herein are believed to have higher purity, less odor, greaterstability, and/or are produced with higher yield.

Further, the choline salt(s) of an organic compound made by the methodsdisclosed herein can have a greater solubility in water and/or anaqueous solution than the organic compound used to react with choline inthe methods disclosed herein and/or than the choline salt(s) of anorganic compound made by other methods. Accordingly, it is expected thatadministering the choline salt(s) of an organic compound made by themethods disclosed herein to a subject will increase the concentration ofthe choline salt(s) of an organic compound in the subject, increaseabsorption, increase bioavailability, and/or increase the amount of thecompound that can be processed by the subject and/or the organisms in asubject (e.g., organisms in the subject's gut) as compared to cholinesalts of an organic compound made by other methods and as compared tothe organic compound alone that is used to react with choline in themethods disclosed herein. Further, administration of the choline salt(s)of an organic compound produced by the methods disclosed herein isexpected to increase the amount of metabolites of the choline salt(s) ofan organic compound produced in a subject.

In one aspect, there is disclosed a method of preparing one or morecholine ellagate compound(s), the compounds can have a low odor and/orthat possesses a reduced rate of choline degradation compared to cholineellagate compound(s) produced by conventional methods. The method caninclude (a) obtaining a liquid suspension of an ellagic acid compound(e.g., ellagic acid dihydrate, ellagic acid, or both); (b) contacting acholine salt with the ellagic acid compound in a liquid solution at a pHof 6.95 to 8 and in a reduced oxygen environment to form a liquidsuspension containing one or more choline ellagate compound(s); (c)cooling the liquid suspension of step (b) to a 25° C. or below; (d)isolating one or more of the choline ellagate compound(s) from theliquid solution; and (e) drying the isolated choline ellagatecompound(s). In some instances, the molar ratio of choline salt toellagic acid compound is 1.9:1 to 2.1:1. The cooling step (c) canfurther include cooling the liquid suspension containing the cholineellagate compound(s) to 0° C. to −80° C. in the dark and protected frommoisture and oxygen. In some instances, the cooling step (c) cools theliquid suspension containing the choline ellagate compound(s) to −20° C.to −80° C. In a particular instance, the contacting in step (b)increases in temperature to a temperature sufficient to dissolve theellagic acid compound and form the choline ellagate compound(s). In someinstances, step (b) is performed at a temperature of less than 100° C.In some instances, the contacting in step (b) is not allowed to increaseover 50° C., preferably it is not allowed to increase over 45° C. Insome instances, the contacting of step (b) increases in temperatureabove the temperature of the environment surrounding the contacting onlythrough the exothermic reaction and/or exothermic dissolving of thecontacting components (e.g. the contacting step is not heated by anexternal source). The suspension containing the choline ellagatecompound(s) can be cooled for more than 0.5 hours, and preferably atleast 5 hours. Isolating one or more of the choline ellagate compound(s)can include (i) filtering (e.g., fast flow filtration) the cholineellagate compound(s) suspension to obtain choline ellagate compound(s)precipitate and a liquid filtrate, where the liquid filtrate includes atleast one dissolved choline ellagate compound and (ii) washing thecholine ellagate compound(s) precipitate in cold ethanol (e.g., of −20°C. and −80° C.). Drying isolated choline ellagate compound(s) caninclude heating the choline ellagate compound(s) precipitate at lessthan 80° C. under vacuum until a constant weight is realized. Duringdrying, the choline ellagate compound(s) precipitate can be agitated.

Isolating one or more of the choline ellagate compound(s) from theliquid solution can further include (iii) forming an alcoholic solutionthat includes the liquid filtrate, the ethanolic wash, or both; and (iv)isolating additional choline ellagate compound(s) precipitate from thealcoholic solution and (v) drying the isolated choline ellagatecompound(s). In some instances, isolating the additional cholineellagate compound(s) composition includes (iv.1) reducing the volume ofthe alcoholic solution; (iv.2) cooling the reduced alcoholic solution toa temperature sufficient to precipitate the additional choline ellagatecompound(s) from the solution; (iv.3) isolating additional cholineellagate compound(s); and (iv.4) drying the isolated choline ellagatecompound(s).

The liquid used in the methods of the present invention can be a solventfor the choline salt and/or the ellagic acid compound. In someinstances, the liquid contains methanol, ethanol, or water, or acombination thereof. The methanol and/or ethanol used in the method ofthe present invention can have a purity of at least 99.5%, preferably100%. In some instances, the choline salt can be a hydroxide salt ofcholine.

The reduced oxygen environment can be obtained by exchanging oxygendissolved in the liquid solution with inert gas (e.g., argon), bydisplacement of an oxygen atmosphere by an inert gas, or by performingthe step(s) in a sealed container (e.g., a container that does not allowroom for a gaseous atmosphere to be present in the container.

The dried choline ellagate compound(s) made by the present invention canbe substantially devoid of free amine and/or trimethylamine, amine-typeodor, and/or has a low odor. In some instances, the choline ellagatecompound(s) includes at least 80 wt. % dicholine ellagate, at least 90wt. % dicholine ellagate, or 99.9 wt. % dicholine ellagate. In someaspects, the choline ellagate compound(s) further include cholinephenolates that are different than dicholine ellagate.

In some instances, the ellagic acid compound used in the method isderived from a source selected from the group consisting of redraspberries, pomegranate, strawberries, and blueberries, and anycombination thereof. In another instance, the ellagic acid compound isderived from a Punica granatum (pomegranate) and has an ellagic acidpurity of 40% or more, preferably 98% or more. In yet another instance,the ellagic acid compound is derived from a tree bark extract.

In another aspect of the invention, a choline ellagate compound(s)formed by any of the methods of the present invention is described. In aparticular aspect, a composition that includes at least one cholineellagate compound made by the method of the present invention isdescribed.

In another aspect of the invention, a method of preparing a choline saltof an organic compound composition is described. The method can include(a) obtaining a liquid suspension of an organic compound capable ofinteracting with choline; (b) contacting a choline salt with the organiccompound in a liquid under a reduced oxygen atmosphere and a pH of 6.95to 8 to form a liquid suspension containing one or more choline salt(s)of the organic compound; (c) cooling the liquid suspension of step (b)to a 25° C. or below; (d) isolating the choline salt(s) of the organiccompound from the liquid suspension; and (e) drying the isolated cholinesalt(s) of the organic compound. The organic compound can be aphytochemical, such as a phenolic compound (e.g., ellagic aciddihydrate, ellagic acid, gallic acid, a vanillic acid, a salicylic acid,syringic acid, a urolithin, or a combination thereof). The cholinesalt(s) of the organic compound composition can be a low odor cholinesalt(s) of the organic compound composition.

The choline salt(s) of an organic compound, such as choline ellagiccompound(s), of the present invention can further include someimpurities. For example, one or more polyphenols, preferably, a diphenolcompound that includes at least two carboxylic groups or a diphenolcompound having at least two lactones. In some instances, thecompositions disclosed herein can further include minimal amounts oftannins (for example, ellagic acid tannin), free ellagic acid, freecholine, or any combination thereof.

The choline salt(s) of an organic compound can have a purity of 95 wt. %or more, or preferable 98 wt. % or more as determined using HighPressure Liquid Chromatograph (HPLC). The low odor choline salt(s) of anorganic compound can have 10 wt. % or less, 5 wt. % or less, 3 wt. % orless, 2 wt. % or less of water, 5 wt % or less of tannins, and/or 5 wt.% or less of other polyphenols.

In some aspects of the invention, compositions that include the cholinesalt(s) of an organic compound, such as choline ellagate compound(s),are described. These choline salt(s) of an organic compound compositionscan include one or more carriers or diluents acceptable for humanconsumption and/or pharmaceutically and/or nutraceutically acceptablecarriers or diluents. These carriers/diluents can be adjuvants,excipients, or vehicles such as preserving agents, fillers,disintegrating agents, wetting agents, emulsifiers, suspending agents,sweeteners, flavorings, fragrance, antibacterial agents, antifungalagents, lubricating agents, vitamins, polymers, siloxane containingcompounds, essential oils, structuring agents, and dispensing agents.Each carrier is acceptable in the sense of being compatible with theother ingredients of the formulation and not injurious to the subject.In some aspects of the invention, the acceptable carrier can include atleast one hydrophilic polymeric compound selected from the groupconsisting of a gum, a cellulose ether, an acrylic resin, a carbohydratecarrier, talc, lactose, mannitol, glucose, water, gelatin, aprotein-derived compound, polyvinyl pyrrolidone, magnesium stearate, andany combination thereof. Non-limiting examples of diluents/carriers areidentified throughout this specification and are incorporated into thissection by reference.

The amounts of such ingredients can range from 0.0001% to 99.9% byweight or volume of the composition, or any integer or range in betweenas disclosed in other sections of this specification, which areincorporated into this paragraph by reference.

In some aspects of the invention, the choline salt(s) of an organiccompound compositions, such as choline ellagate compound(s)compositions, can be formulated as a food, a food ingredient, a drink, apowder, a tablet, a gel-cap, a bead, an edible tablet, a gelatin, alotion, a transdermal patch, or a liquid solution for oraladministration. In some aspects of the invention, the formulatedcomposition can be comprised in a solid nanoparticle, a lipid-containingnanoparticle, a lipid-based carrier, a sealed conduit, a straw, sealedbag, or any combination thereof. In other aspects of the invention, thecomposition can be formulated for administration by injection.

Kits that include the choline salt(s) of an organic compound, such ascholine ellagate compound(s), of the present invention are alsocontemplated. In certain embodiments, the choline salt(s) of an organiccompound are included in a container. The container can be a bottle,dispenser, package, or a straw. The container can dispense apredetermined amount of the composition. In certain aspects, the cholinesalt(s) of an organic compound are dispensed as a pill, a tablet, acapsule, a transdermal patch, an edible chew, a cream, a lotion, a gel,spray, mist, dollop, a powder, or a liquid. The container can includeindicia on its surface. The indicia can be a word, an abbreviation, apicture, or a symbol.

In some aspects of the present invention, methods of using the cholinesalt(s) of an organic compound, such as choline ellagate compound(s), ofthe present invention are disclosed. In some instances, the cholinesalt(s) of an organic compound, such as choline ellagate compound(s),can be used to increase metabolites of the choline salt(s) of an organiccompound. The metabolites can include urolithins. In some instances, theurolithin production is increased in the subject as compared to theamount of urolithin production caused by administering an equal amountof ellagic acid, a choline salt(s) of an organic compound produced byanother method, and/or a choline ellagate compound produced by anothermethod, on a mole to mole basis. In some instances, the choline salt(s)of an organic compound, such as choline ellagate compound(s), can beused in a method to treat a subject by administering an effective amountof a choline salt of an organic compound produced by the methodsdisclosed herein to the subject. In some instances, administering thecholine salt(s) of an organic compound increases urolithin production inthe subject. In some instances, urolithin production is increased in thesubject as compared to the amount of urolithin production caused byadministering an equal amount of ellagic acid, a choline salt of anorganic compound produced by another method, and/or a choline ellagatecompound produced by another method, on a mole to mole basis. In someinstances, the subject is treated for a condition that can be improvedby an increase in at least one urolithin concentration in the subject.In some instances, the subject is treated for a degenerative nervecondition or is treated to attempt to prevent a degenerative nervecondition. The degenerative nerve condition can be Alzheimer's disease,Parkinson's disease, and/or Huntington's disease. In some instances, thesubject is treated for a condition caused by decreased mitophagy. Thecondition caused by mitophagy can be a cancer, a metabolic disorder,muscle atrophy, and/or inflammation. In some instances, a method ofincreasing mitophagy and/or decreasing neurodegeneration in a subject isdisclosed by administering the choline salt(s) of an organic compoundproduced by the methods disclosed herein.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method or composition of theinvention, and vice versa. Furthermore, compositions of the inventioncan be used to achieve methods of the invention.

Also contemplated is a product that includes the choline salt(s) of anorganic compound of the present invention. In non-limiting aspects, theproduct can be a food, food ingredient, nutraceutical, and/orpharmaceutical product. The product can be those described in othersections of this specification or those known to a person of skill inthe art. Non-limiting examples of products include a food, supplement,pill, a tablet, an edible chew, a capsule, a cream, a lotion, a gel, aspray, a mist, a dissolving film, a transdermal patch, a liquid, a food,a nutraceutical, a cosmetic, etc.

“Therapeutic agent” and “nutraceutical agent” encompasses the cholinesalt(s) of an organic compound disclosed herein. It also encompassessuch compounds together with pharmaceutically and nutraceuticallyacceptable salts thereof. Useful salts are known to those skilled in theart and include salts with inorganic acids, organic acids, inorganicbases, or organic bases. Therapeutic agents and nutraceutical agentsuseful in the present invention are those compounds that affect adesired, beneficial, and often pharmacological, effect uponadministration to a human or an animal, whether alone or in combinationwith other pharmaceutical or nutraceutical excipients or inertingredients.

The term “ellagic acid” refers to the ellagic acid, salts thereof,analogues thereof, derivatives thereof, or salt forms of any analogue orderivative thereof. A non-limiting example of a ellagic acid analogue isa urolithin.

The term “ellagic acid compound” refers to the ellagic acid, ellagicacid dihydrate, or both, salts thereof, analogues thereof, derivativesthereof, or salt forms of any analogue or derivative thereof.

The term “ellagic acid dihydrate compound” refers to the ellagic aciddihydrate, analogues thereof, salts thereof, derivatives thereof, orsalt forms of any analogue or derivative thereof.

The term “choline” refers to the choline, salts thereof, analoguesthereof, derivatives thereof, or salt forms of any analogue orderivative thereof.

The term “choline ellagate compound” refers to choline salts of anellagic acid compound. The choline ellagate compound can be cholineellagate, dicholine ellagate, etc.

The term “substantially” and its variations are defined as being largelybut not necessarily wholly what is specified as understood by one ofordinary skill in the art, and in one non-limiting embodimentsubstantially refers to ranges within 10%, within 5%, within 1%, orwithin 0.5%.

“Patient,” “subject,” or “individual” refers to a mammal (e.g., human,primate, dog, cat, bovine, ovine, porcine, equine, mouse, rate, hamster,rabbit, or guinea pig). In particular aspects, the patient, subject, orindividual is a human.

“Inhibiting” or “reducing” or any variation of these terms includes anymeasurable decrease or complete inhibition to achieve a desired result.

“Effective” or “treating” or “preventing” or any variation of theseterms means adequate to accomplish a desired, expected, or intendedresult.

“Analogue” and “analog,” when referring to a compound, refers to amodified compound wherein one or more atoms have been substituted byother atoms, or wherein one or more atoms have been deleted from thecompound, or wherein one or more atoms have been added to the compound,or any combination of such modifications. Such addition, deletion orsubstitution of atoms can take place at any point, or multiple points,along the primary structure comprising the compound.

“Derivative,” in relation to a parent compound, refers to a chemicallymodified parent compound or an analogue thereof, wherein at least onesubstituent is not present in the parent compound or an analoguethereof. One such non-limiting example is a parent compound which hasbeen covalently modified. Typical modifications are amides,carbohydrates, alkyl groups, acyl groups, esters, pegylations and thelike.

A “therapeutically equivalent” drug is one that has essentially the sameeffect in the treatment of a disease or condition as one or more otherdrugs. A drug that is therapeutically equivalent may or may not bechemically equivalent, bioequivalent, or generically equivalent.

“Parenteral injection” refers to the administration of small moleculedrugs via injection under or through one or more layers of skin or mucusmembranes of an animal, such as a human.

“Bioavailability” refers to the extent to which the therapeutic agent,such as dicholine ellagate, is absorbed from the formulation.

“Systemic,” with respect to delivery or administration of a therapeuticagent, such as one or more choline ellagate compounds, to a subject,that therapeutic agent is detectable at a biologically significant levelin the blood plasma of the subject.

“Controlled release” refers to the release of the therapeutic agent atsuch a rate that blood (e.g., plasma) concentrations are maintainedwithin the therapeutic range, but below toxic concentrations over aperiod of time of about one hour or longer, preferably 12 hours orlonger.

“Nutraceutically acceptable carrier” refers to a nutraceuticallyacceptable solvent, suspending agent or vehicle for delivering acompound, salt, or crystal of the present invention to a mammal such asan animal or human.

“Nutraceutically acceptable” ingredient, excipient or component is onethat is suitable for use with humans and/or animals without undueadverse side effects (such as toxicity, irritation and allergicresponse) commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable carrier” refers to a pharmaceuticallyacceptable solvent, suspending agent or vehicle for delivering a drugcompound of the present invention to a mammal such as an animal orhuman.

“Pharmaceutically acceptable” ingredient, excipient or component is onethat is suitable for use with humans and/or animals without undueadverse side effects (such as toxicity, irritation and allergicresponse) commensurate with a reasonable benefit/risk ratio.

The term “mammal” or “mammalian” includes murine (e.g., rats, mice)mammals, rabbits, cats, dogs, pigs, and primates (e.g., monkey, apes,humans). In particular aspects in the context of the present invention,the mammal can be a murine mammal or a human.

The term “about” or “approximately” or “substantially unchanged” aredefined as being close to as understood by one of ordinary skill in theart, and in one non-limiting embodiment the terms are defined to bewithin 10%, preferably within 5%, more preferably within 1%, and mostpreferably within 0.5%. Further, “substantially non-aqueous” refers toless than 5%, 4%, 3%, 2%, 1%, or less by weight or volume of water.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.”

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The compositions and methods for their use can “comprise,” “consistessentially of,” or “consist of” any of the ingredients or stepsdisclosed throughout the specification. With respect to the transitionalphase “consisting essentially of,” in one non-limiting aspect, a basicand novel characteristic of the compositions and methods disclosed inthis specification includes the low odor of the choline compositionsand/or increase the stability of choline compositions, etc.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the examples,while indicating specific embodiments of the invention, are given by wayof illustration only. Additionally, it is contemplated that changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1 depicts a ¹³C NMR spectrum for an embodiment of the cholineellagate compound(s) disclosed herein.

FIG. 2 depicts the settings for the ¹³C NMR spectrum depicted in FIG. 1.

DETAILED DESCRIPTION

Disclosed herein are methods of making choline salt(s) of an organiccompound such as choline ellagate compound(s), uses of such compounds,and compositions containing such compounds. It has been surprisinglyfound that the choline salt(s) of an organic compound disclosed hereinhave less odor in comparison with choline, salts thereof, and cholinesalt(s) of an organic compound made by other methods. Not to be bound bytheory, it is believed that the choline salt(s) of an organic compoundsmade by the methods disclosed herein can have lower degradationproducts, lower impurities, and/or lower amine-type compounds (e.g.,trimethylamine, ammonium compounds). Thus, using the choline salt(s) ofan organic compound made by the methods disclosed herein can provide abenefit of higher purity, less odor, and/or greater stability. Further,disclosed herein is that the choline salt(s) of an organic compound madeby the methods disclosed herein can have a greater solubility in waterand/or an aqueous solution than the organic compound used to contactcholine in the methods disclosed herein and/or than the choline salt(s)of an organic compound made by other methods. Accordingly, it isexpected that administering to a subject the choline salt(s) of anorganic compound made by the methods disclosed herein will increase thesolubilized concentration of the choline salt(s) of an organic compoundin the subject, increase absorption, increase bioavailability, and/orincrease the amount of the compound that can be processed by the subjectand/or the organisms in a subject (e.g., organisms in the subject'sgut), etc. as compared to choline salts of an organic compound made byother methods and as compared to the organic compound alone that is usedto contact choline in the methods disclosed herein. Further,administration to a subject of the choline salt(s) of an organiccompound produced by the methods disclosed herein is expected toincrease the amount of metabolites of the choline salt(s) of an organiccompound. Accordingly, administration of the choline salt(s) of anorganic compound produced by the methods disclosed herein is expected toprovide a more effective therapy than using choline salt(s) of anorganic compound made by other methods.

A. Choline Salt of an Organic Compound

The choline salt of an organic compound of the present invention can beformed by using choline and an organic compound, such as an ellagic acidcompound, ellagic acid, and/or ellagic acid dihydrate. In a preferredembodiment, the choline salt of an organic compound is dicholineellagate with a purity of greater than 95.0 wt. %. 1. Organic CompoundCapable Of Interacting With Choline

The choline salt of an organic compound of the present invention can beformed by using an organic compound capable of interacting with choline.Non-limiting examples of the organic compounds include phytochemicalssuch as alkaloids, organosulfurs, phenolics, carbohydrates, proteins,and lipids. In some instances, the organic compound is a phenoliccompound. Non-limiting examples of phenolic compounds are stilbenes,tannins, lignans, phenolic acids, phenolic aldehydes, and flavonoids. Insome instances, the organic compound is a tannin. Non-limiting examplesof tannins include proanthocyanidins and hydrolyzable tannins such asgallotannins and ellagitannins which can include ellagic acid andurolithins such as urolithin A, urolithin B, urolithin C, and urolithinD. The organic compounds can be made by known synthetic methods and/orby isolation from a natural source. The organic compound can have apurity of 40% to 100%. In a preferred embodiment, the organic compoundhas a purity of greater than 98.0 wt. % and is a crystalline powder 2.Ellagic Acid or Ellagic Acid Dihydrate

The choline ellagate compound of the present invention can be formed byusing ellagic acid or ellagic acid dihydrate. The ellagic acid orellagic acid dihydrate compound can have a purity of 40% to 100%. In apreferred embodiment, the ellagic acid or ellagic acid dihydratecompound has a purity of greater than 98.0 wt. % and is a crystallinepowder.

The ellagic acid or ellagic acid dihydrate can be made through knownsynthetic methods such as methylation and acylation reactions asdescribed in U.S. Pat. No. 5,066,571 to Caufield, which is incorporatedherein by reference. For example, ellagic acid or ellagic acid dihydratecan be prepared by oxidative coupling of gallic acid to form thedicarboxylic acid form of ellagic acid, followed by lactonization toform the desired compound and then crystallized in the presence orabsence of water. Derivatives of ellagic acid or ellagic acid dihydratecan be made using known reactions for amidization, esterification, etc.

In some aspects of the invention, the ellagic acid or ellagic aciddihydrate can be isolated from extracts of fruits and plants.Non-limiting examples of fruits include red raspberries, pomegranate,strawberries, and blueberries. Non-limiting examples of plants includeextract of tree bark. Non-limiting examples of sources of tree barkinclude Anisophyllea dichostyla; Elaeocarpus parvifolius; Eucalyptusglobulus; Platycarya strobilacea; Punica granatum; a species of thegenus Castanea; a species of the genus Terminalia; and a species of thegenus Quercus. In some aspects of the invention, by-products of thepaper industry may be used as a source for ellagic acid and/orellagitannins. Plants and fruits contain the natural productellagitannins. The ellagitannins can be extracted from the plants andfruits using known extraction methods, such as contacting the treesawdust with an alcohol at ambient temperature with agitation, followedby filtration to obtain the extract. The extract can includeellagitannins, ellagic acid and other products. The extract can besubjected to acid hydrolysis conditions to hydrolyze the ellagitanninsto the open acid form of ellagic acid, followed by subsequentlactonization under acid or basic conditions to produce the ellagic acidor ellagic acid dihydrate. Ellagic acid and ellagic acid dihydrate iscommercially available from many chemical suppliers. Non-limitingexamples of suppliers are Sigma-Aldrich (USA) and TCI Fine Chemicals(China/Japan).

2. Choline

Choline can be made or obtained through commercial vendors. The cholinesource can be a chloride or hydroxide salt of choline. In a preferredembodiment, the choline compound is hydroxide salt of choline and has apurity of greater than 95.0 wt. %. In some aspects of the invention thecholine can be made through known synthetic methods. In some aspects ofthe invention the choline can be isolated from extracts of an organism,such as fruits or plants. 3. Method of Making Choline Salts of anOrganic Compound and/or Choline

Ellagate Compound Possessing a Decreased Rate of Choline Degradationand/or a Low Odor

Choline salts of an organic compound, such as choline ellagatecompound(s), of the present invention can be formed by contacting acholine salt with an organic compound, such as an ellagic acid compound.In some instances, the ellagic acid compound can be ellagic aciddihydrate, ellagic acid, or both. The organic compound can be contactedwith a choline salt, such as a hydroxide salt of choline, in a liquidenvironment (e.g., aqueous, methanolic, ethanolic, etc.) with reducedoxygen and a pH of between 5 to 9, preferably between 6.5 to 8.5, morepreferably between 7.0 to 7.5 to form a liquid suspension containing acholine salt of an organic compound. In some instances, the molar ratioof the choline salt to the organic compound in the reaction is 3:1 to0.3:1, preferably 3:1 to 1.5:1, more preferably 1.9:1 to 2.1:1. Theenvironment with reduced oxygen can be obtained by any means known inthe art. In non-limiting examples, the environment with reduced oxygencan be obtained by exchanging oxygen dissolved in the liquid solutionwith inert gas (e.g., argon), by displacement of an oxygen atmosphere byan inert gas, or by performing the step(s) in a container that does notallow room for a gaseous atmosphere to be present in the container(e.g., a sealed container with no head space). Upon addition of theorganic compound to the choline salt, the temperature of the contactingstep can increase to a temperatures such that the ingredients dissolveand/or form the choline salt of an organic compound, such as a cholineellagate compound. In non-limiting examples, the temperature of thecontacting step can increase to a temperature of less than 100° C., 75°C., 50° C., or 45° C. In a preferred embodiment, the contacting step canbe 50° C. or less. In a more preferred embodiment, the temperature isincreased to above room temperature only by the exothermic reaction thatforms the choline salt(s) of the organic compound and/or is caused bythe dissolving of the organic compound or choline salt. In someembodiments, the contacting step temperature is controlled to less than100° C. by external cooling of the reaction vessel. As choline salt(s)of the organic compound form, it can precipitate from solution.

The liquid suspension can be cooled to precipitate or cause furtherprecipitation of the choline salt(s) of the organic compound. Thesuspension can be cooled to 25° C. or lower, or to less than 10° C., 4°C., 0° C., −15° C., or −20° C. Preferably, the suspension is cooled tobetween −20° C. and −80° C. The suspension can be cooled in one or moresteps. In non-limiting aspects, the suspension can be cooled to at orbelow 25° C. for at least 5 hours and then cooled to less than 0° C. forat least 15 minutes. Preferably, the suspension is cooled to −20° C. to−80° C. The cooling and precipitation can occur while the suspension andthe precipitate are protected from light, moisture, and/or oxygen. Innon-limiting examples, the suspension and the precipitate are protectedfrom oxygen by exchanging oxygen dissolved in the liquid solution withinert gas (e.g., argon), by displacement of an oxygen atmosphere by aninert gas, or by performing the step(s) in a container that does notallow room for a gaseous atmosphere to be present in the container.

One or more of the choline salt(s) of the organic compound precipitatedfrom the liquid solution can be isolated. The precipitate can beisolated by any means known in the art. In non-limiting examples, theprecipitate can be isolated by filtration, centrifugation, ordecantation. In a preferred embodiment, the precipitate is isolated byfiltration. In some instances, the collection can be performed by vacuumfiltration, centrifugal filtration, or gravity filtration. In a morepreferred embodiment, the precipitate is isolated by fast flowfiltration. The remaining solution after isolation (“liquid flowthrough”) of the choline salt(s) of the organic compound precipitate canbe saved for further processing.

In a non-limiting embodiment, the isolated choline salt(s) of theorganic compound can be washed by ethanol. The ethanol can be coldethanol. The temperature of the ethanol can be a less than 10° C.,preferably less than or equal to 0° C., more preferably at or less than−20° C., such as between −20° C. and −80° C., or −40° C. and −75° C.,−30° C. and −70° C. The ethanol can be 95% or more pure ethanol,preferably, the ethanol is 100% pure ethanol. The ethanolic wash can besaved for further processing. Not to be bound by theory, washing thecholine salt(s) of the organic compound under cold conditions caninhibit degradation of the choline salt(s) of the organic compound,while removing excess choline from the choline salt(s) of the organiccompound.

The isolated choline salt(s) of the organic compound can be dried. Thecholine salt(s) of the organic compound can be dried by any means knownby one of skill in the art. In non-limiting examples, the cholinesalt(s) of the organic compound can be dried by heating the cholinesalt(s) of the organic compound, placing the choline salt(s) of theorganic compound under vacuum, or a combination of the two. In apreferred embodiment the choline salt(s) of the organic compound can bedried at less than 80° C. under vacuum until a constant weight isrealized. During drying, the choline salt(s) of the organic compoundprecipitate can be agitated. No to be bound by theory, it is believedthat drying the choline salt(s) of the organic compound at temperaturesof less than can 80° C. can inhibit degradation of the choline salt(s)of the organic compound and, thus producing a low odor compound.

Choline salt(s) of the organic compound can be isolated from the liquidflow through, the ethanolic wash, or a combination of the two byprecipitating choline salt(s) of the organic compound from thesolution(s). In some instances, isolating the additional choline salt(s)of the organic compound includes reducing the volume of the solution(s).The reduction can be done by any method known in the art, such asheating the solution(s), placing under vacuum, etc. In a preferredembodiment the solutions(s) are reduced by heating to or below 100° C.In some embodiments, one or more of the choline salt(s) of the organiccompound are isolated. The choline salt(s) of the organic compound canbe isolated in a manner similar to that described elsewhere herein suchas, but not limited to, by cooling to form additional precipitate andthen filtering. In some instances, the filtrate therefrom (“reducedfiltrate”) is saved for further processing. In some instances, thecholine salt(s) of the organic compound isolated are dried. In someinstances, the choline salt(s) of the organic compound isolated aredried in a similar manner to that described elsewhere herein such as,but not limited to, by heating to less than 80° C. under vacuum until aconstant weight is realized.

Choline salt(s) of the organic compound can be isolated from the reducedfiltrate. The choline salt(s) of the organic compound can be isolated byany means known in the art. In a non-limiting example, the cholinesalt(s) of the organic compound can be isolated from the reducedfiltrate by further reducing the volume of the reduced filtrate. In apreferred embodiment, the reduced filtrate is heated to less than 80° C.under vacuum until a constant weight is realized.

In some instances, the choline salt(s) of the organic compound, such ascholine ellagate compound(s), made by the present invention aresubstantially devoid of free amine and/or trimethylamine, has a lowodor, and/or the choline therein degrades at a rate slower than that ofcholine salt(s) of the organic compound made by other methods. In someinstances, the choline salt(s) of the organic compound includes at least80 wt. % dicholine ellagate, at least 90 wt. % dicholine ellagate, or99.9 wt. % dicholine ellagate. The choline salt(s) of the organiccompound can, but is not limited to, comprises choline phenolates thatare different than dicholine ellagate.

4. Uses of Choline salt(s) of an organic compound

The choline salt(s) of an organic compound, such as choline ellagatecompound(s), disclosed herein can substitute or be combined with cholinesalt(s) of an organic compound known in the art and used in any of theuses known in the art for choline salt(s) of an organic compound. It isdisclosed herein that the choline salt(s) of an organic compound made bythe methods disclosed herein can have lower degradation products, lowerimpurities, and/or lower amine-type compounds (e.g., trimethylamine,ammonium compounds). Thus, using the choline salt(s) of an organiccompound made by the methods disclosed herein provides a benefit ofhigher purity, less odor, and/or greater stability.

Further, disclosed herein is that the choline salt(s) of an organiccompound made by the methods disclosed herein have a greater solubilityin water and/or an aqueous solution than the organic compound used toreact with choline in the methods disclosed herein and/or cholinesalt(s) of an organic compound made by other methods. In some instances,the choline ellagate compound made by the methods disclosed herein havea greater solubility in water and/or an aqueous solution than an ellagicacid compound and/or a choline ellagate compound made by other methods.

Not to be bound by theory, the increased solubility in water of thecholine salt(s) of an organic compound is believed to increase theconcentration of the choline salt(s) of an organic compound in asubject, increase absorption, increase bioavailability, and/or increasethe amount of the compound that can be processed by the subject and/orthe organisms in a subject (e.g. the subject's gut), etc. as compared tocholine salts of an organic compound made by other methods and ascompared to the organic compound alone that is used to contact cholinein the methods disclosed herein. Accordingly, administration to asubject of the choline salt(s) of an organic compound produced by themethods disclosed herein is expected to increase the amount ofmetabolites of the choline salt(s) of an organic compound, choline,and/or the organic compound that is used to contact choline in themethods disclosed herein. For example, it is expected thatadministration of the choline ellagate compound(s) produced by themethods disclosed herein will increase the amount of urolithins producedin the subject when compared to administration of an ellagic acidcompound alone or a choline ellagate compound produced by a differentmethod.

Not to be bound by theory, the increased concentration of the cholinesalt(s) of an organic compound in a subject's gut, increased absorption,increased bioavailability, increased amount of the compound that can beprocessed by the gut and/or the organisms in a subject's gut, and/orincreased amount of metabolites produced in the subject (such asurolithins), etc. is expected to increase the efficacy of treatment of asubject over treatment with the organic compound that is used to contactcholine in the methods disclosed herein (such as ellagic acid) or acholine salt of an organic compound (such as a choline ellagatecompound) produced by a different method. As a non-limiting example,administration of choline ellagate compound(s) disclosed herein canincrease urolithin production in a subject and can treated or be used toattempt to prevent a condition that can be improved by an increase in atleast one urolithin concentration in the subject. The condition can be adegenerative nerve condition such as Alzheimer's disease, Parkinson'sdisease, and/or Huntington's disease. The condition can be a conditioncaused by decreased mitophagy, such as a cancer, a metabolic disorder,muscle atrophy, aging, and/or inflammation.

B. Amounts of Ingredients

It is contemplated that the compositions comprising choline salt(s) ofan organic compound of the present invention can include any amount ofthe ingredients discussed in this specification. The compositions canalso include any number of combinations of additional ingredientsdescribed throughout this specification (e.g., stabilizers, fillers,pharmaceutically acceptable salts, and/or additional pharmaceuticalingredients). The concentrations of the any ingredient within thecompositions can vary. In non-limiting embodiments, for example, thecompositions can comprise, consisting essentially of, or consist of, intheir final form, for example, at least about 0.0001%, 0.0002%, 0.0003%,0.0004%, 0.0005%, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.0010%, 0.0011%,0.0012%, 0.0013%, 0.0014%, 0.0015%, 0.0016%, 0.0017%, 0.0018%, 0.0019%,0.0020%, 0.0021%, 0.0022%, 0.0023%, 0.0024%, 0.0025%, 0.0026%, 0.0027%,0.0028%, 0.0029%, 0.0030%, 0.0031%, 0.0032%, 0.0033%, 0.0034%, 0.0035%,0.0036%, 0.0037%, 0.0038%, 0.0039%, 0.0040%, 0.0041%, 0.0042%, 0.0043%,0.0044%, 0.0045%, 0.0046%, 0.0047%, 0.0048%, 0.0049%, 0.0050%, 0.0051%,0.0052%, 0.0053%, 0.0054%, 0.0055%, 0.0056%, 0.0057%, 0.0058%, 0.0059%,0.0060%, 0.0061%, 0.0062%, 0.0063%, 0.0064%, 0.0065%, 0.0066%, 0.0067%,0.0068%, 0.0069%, 0.0070%, 0.0071%, 0.0072%, 0.0073%, 0.0074%, 0.0075%,0.0076%, 0.0077%, 0.0078%, 0.0079%, 0.0080%, 0.0081%, 0.0082%, 0.0083%,0.0084%, 0.0085%, 0.0086%, 0.0087%, 0.0088%, 0.0089%, 0.0090%, 0.0091%,0.0092%, 0.0093%, 0.0094%, 0.0095%, 0.0096%, 0.0097%, 0.0098%, 0.0099%,0.0100%, 0.0200%, 0.0250%, 0.0275%, 0.0300%, 0.0325%, 0.0350%, 0.0375%,0.0400%, 0.0425%, 0.0450%, 0.0475%, 0.0500%, 0.0525%, 0.0550%, 0.0575%,0.0600%, 0.0625%, 0.0650%, 0.0675%, 0.0700%, 0.0725%, 0.0750%, 0.0775%,0.0800%, 0.0825%, 0.0850%, 0.0875%, 0.0900%, 0.0925%, 0.0950%, 0.0975%,0.1000%, 0.1250%, 0.1500%, 0.1750%, 0.2000%, 0.2250%, 0.2500%, 0.2750%,0.3000%, 0.3250%, 0.3500%, 0.3750%, 0.4000%, 0.4250%, 0.4500%, 0.4750%,0.5000%, 0.5250%, 0.0550%, 0.5750%, 0.6000%, 0.6250%, 0.6500%, 0.6750%,0.7000%, 0.7250%, 0.7500%, 0.7750%, 0.8000%, 0.8250%, 0.8500%, 0.8750%,0.9000%, 0.9250%, 0.9500%, 0.9750%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%,1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%,2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%,4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%,5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%,6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%,7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%,8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%,10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%,24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, or 99% or any range derivable therein, of atleast one of the ingredients that are mentioned throughout thespecification and claims. In non-limiting aspects, the percentage can becalculated by weight or volume of the total composition. A person ofordinary skill in the art would understand that the concentrations canvary depending on the addition, substitution, and/or subtraction ofingredients in a given composition.

It is contemplated that the choline salt(s) of an organic compound ofthe present invention can be prepared by contacting an organic compoundat any ratio to choline. In non-limiting aspects, the ratio of organiccompound, such as an ellagic acid compound, to choline in the reactionof the present invention can be 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4,1:5, or any range derivable therein. In non-limiting aspects, the ratiocan be calculated by moles to moles.

C. Additional Components

The choline salt(s) of an organic compound of the present invention canbe formulated into any suitable composition form for administration to ahuman or non-human animal patient, such as a food, pharmaceutical, ornutraceutical.

The composition may consist of choline salt(s) of an organic compound,such as a choline ellagate compound(s), alone or may include cholinesalt(s) of an organic compound and any suitable additional component,such as one or more food ingredient, or pharmaceutically ornutraceutically acceptable carriers, diluents, adjuvants, excipients, orvehicles, such as foods ingredients, preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavoring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispensing agents, depending on the nature of the mode of administrationand dosage forms. Each carrier must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the patient.

1. Excipients

Excipients employed in the compositions of the present invention can besolids, semi-solids, liquids or combinations thereof. Preferably, theexcipients are solids. Compositions of the invention containingexcipients can be prepared by any known technique that includes, forexample, admixing an excipient with the choline salt(s) of an organiccompound. A pharmaceutical composition of the invention contains adesired amount of the choline salt(s) of an organic compound per doseunit and, if intended for oral administration, can be in the form, forexample, of a tablet, a caplet, a pill, a hard or soft capsule, alozenge, a cachet, a dispensable powder, granules, a suspension, anelixir, a dispersion, or any other form reasonably adapted for suchadministration. If intended for parenteral administration, it can be inthe form, for example, of a suspension or transdermal patch. If intendedfor rectal administration, it can be in the form, for example, of asuppository. Presently preferred are oral dosage forms that are discretedose units each containing a predetermined amount of the choline salt(s)of an organic compound such as tablets or capsules.

2. Carriers/Diluents

Suitable carriers or diluents illustratively include, but are notlimited to, either individually or in combination, lactose, includinganhydrous lactose and lactose monohydrate; starches, including directlycompressible starch and hydrolyzed starches (e.g., CELUTAB™ and EMDEX™),mannitol, sorbitol, xylitol, dextrose (e.g., CERELOSE™ 2000) anddextrose monohydrate, dibasic calcium phosphate dihydrate, sucrose-baseddiluents, confectioner's sugar, monobasic calcium sulfate monohydrate,calcium sulfate dihydrate, granular calcium lactate trihydrate,dextrates, inositol, hydrolyzed cereal solids, amylose, cellulosesincluding microcrystalline cellulose, food grade sources of alpha- andamorphous cellulose (e.g., RexcelJ), powdered cellulose,hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC),calcium carbonate, glycine, clay, bentonite, block co-polymers,polyvinylpyrrolidone, and the like. Such carriers or diluents, ifpresent, constitute in total about 5% to about 99.999%, about 10% toabout 85%, and 20% to about 80%, of the total weight of the composition.The carrier, carriers, diluent, or diluents selected preferably exhibitsuitable flow properties and, where tablets are desired,compressibility.

3. Disintegrant

Compositions of the invention optionally can include one or morepharmaceutically acceptable disintegrants as excipients, particularlyfor tablet formulations. Suitable disintegrants include, but are notlimited to, either individually or in combination, starches, includingsodium starch glycolate and pregelatinized corn starches, clays,celluloses such as purified cellulose, microcrystalline cellulose,methylcellulose, carboxymethylcellulose and sodiumcarboxymethylcellulose, croscarmellose sodium, alginates, crospovidone,and gums such as agar, guar, locust bean, karaya, pectin and tragacanthgums. Disintegrants may be added at any suitable step during thepreparation of the composition, particularly prior to granulation orduring a lubrication step prior to compression. Such disintegrants, ifpresent, constitute in total about 0.2% to about 30%, preferably about0.2% to about 10%, and more preferably about 0.2% to about 5%, of thetotal weight of the composition.

4. Binders

The compositions of the present invention can include binding agents oradhesives particularly for tablet formulations. Such binding agents andadhesives preferably impart sufficient cohesion to the powder beingtableted to allow for normal processing operations such as sizing,lubrication, compression and packaging, but still allow the tablet todisintegrate and the composition to be absorbed upon ingestion. Suchbinding agents may also prevent or inhibit crystallization orrecrystallization of choline salt(s) of an organic compound of thepresent invention once the salt has been dissolved in a solution.Suitable binding agents and adhesives include, but are not limited to,either individually or in combination, acacia; tragacanth, sucrose,gelatin, glucose, starches such as, but not limited to, pregelatinizedstarches, celluloses such as, but not limited to, methylcellulose andcarmellose sodium, alginic acid and salts of alginic acid; magnesiumaluminum silicate, PEG, guar gum, polysaccharide acids, bentonites,povidone, polymethacrylates, HPMC, hydroxypropylcellulose, andethylcellulose. Such binding agents and/or adhesives, if present,constitute in total about 0.5% to about 25%, preferably about 0.75% toabout 15%, and more preferably about 1% to about 10%, of the totalweight of the pharmaceutical composition. Many of the binding agents arepolymers comprising amide, ester, ether, alcohol or ketone groups and,as such, can be included in pharmaceutical compositions of the presentinvention. Polyvinylpyrrolidones is an non-limiting example of a binderused for slow release tablets. Polymeric binding agents can have varyingmolecular weight, degrees of crosslinking, and grades of polymer.Polymeric binding agents can also be copolymers, such as blockco-polymers that contain mixtures of ethylene oxide and propylene oxideunits. Variation in these units' ratios in a given polymer affectsproperties and performance

5. Wetting Agents

Wetting agents can be used in the compositions of the present invention.Wetting agent can be selected to maintain the choline salt(s) of anorganic compound in close association with water, a condition that isbelieved to improve bioavailability of the composition. Such wettingagents can also be useful in solubilizing or increasing the solubilityof choline salt(s) of an organic compound. Surfactants can be used aswetting agents. Non-limiting examples of surfactants that can be used aswetting agents in compositions of the invention include quaternaryammonium compounds, for example benzalkonium chloride, benzethoniumchloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate,polyoxyethylene alkylphenyl ethers, poloxamers (polyoxyethylene andpolyoxypropylene block copolymers), polyoxyethylene fatty acidglycerides and oils, for example polyoxyethylene (8) caprylic/capricmono- and diglycerides, polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil, polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether,polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate, polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80, propylene glycol fatty acid esters, for examplepropylene glycol laurate, sodium lauryl sulfate, fatty acids and saltsthereof, for example oleic acid, sodium oleate and triethanolamineoleate, glyceryl fatty acid esters, for example glyceryl monostearate,sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate,sorbitan monopalmitate and sorbitan monostearate, tyloxapol, andmixtures thereof. Such wetting agents, if present, constitute in totalabout 0.25% to about 15%, preferably about 0.4% to about 10%, and morepreferably about 0.5% to about 5%, of the total weight of thepharmaceutical composition.

6. Lubricants

Lubricants can be included in the compositions of the present invention.Suitable lubricants include, but are not limited to, either individuallyor in combination, glyceryl behapate, stearic acid and salts thereof,including magnesium, calcium and sodium stearates; hydrogenatedvegetable oils, colloidal silica, talc, waxes, boric acid, sodiumbenzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine,PEG (e.g., CARBOWAX™ 4000 and CARBOWAX™ 6000 of the Dow ChemicalCompany), sodium oleate, sodium lauryl sulfate, and magnesium laurylsulfate. Such lubricants, if present, constitute in total about 0.1% toabout 10%, preferably about 0.2% to about 8%, and more preferably about0.25% to about 5%, of the total weight of the pharmaceuticalcomposition.

7. Other Agents

Surfactant, emulsifier, or effervescent agents can be used in thecompositions.

Emulsifying agents can be used to help solubilize the ingredients withina soft gelatin capsule. Non-limiting examples of the surfactant,emulsifier, or effervescent agent include D-sorbitol, ethanol,carrageenan, carboxyvinyl polymer, carmellose sodium, guar gum,glycerol, glycerol fatty acid ester, cholesterol, white beeswax, dioctylsodium sulfosuccinate, sucrose fatty acid ester, stearyl alcohol,stearic acid, polyoxyl 40 stearate, sorbitan sesquioleate, cetanol,gelatin, sorbitan fatty acid ester, talc, sorbitan trioleate, paraffin,potato starch, hydroxypropyl cellulose, propylene glycol, propyleneglycol fatty acid ester, pectin, polyoxyethylene (105) polyoxypropylene(5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol,polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenatedcastor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol400, octyldodecyl myristate, methyl cellulose, sorbitan monooleate,glycerol monostearate, sorbitan monopalmitate, sorbitan monolaurate,lauryl dimethylamine oxide solution, sodium lauryl sulfate,lauromacrogol, dry sodium carbonate, tartaric acid, sodium hydroxide,purified soybean lecithin, soybean lecithin, potassium carbonate, sodiumhydrogen carbonate, medium-chain triglyceride, citric anhydride, cottonseed oil-soybean oil mixture, and liquid paraffin.

8. Food ingredients

Food ingredients can be used in the compositions. Food ingredientsinclude ingredients that provide nutritive, structural, textural, odor,flavor, or therapeutic properties suitable for consumption by a subject.Non-limiting examples of food ingredients include flours, sugars,juices, water, dairy products, gums, salts, etc.

D. Vehicles

Various delivery systems are known in the art and can be used toadminister a therapeutic agent or composition of the invention, e.g.,encapsulation in liposomes, microparticles, microcapsules,receptor-mediated endocytosis and the like. Methods of administrationinclude, but are not limited to, parenteral, intra-arterial,intramuscular, intravenous, intranasal, and oral routes. Thepharmaceutical compositions can be provided in the form of tablets,lozenges, granules, capsules, pills, ampoule, suppositories or aerosolform. The pharmaceutical compositions can also be provided in the formof suspensions, solutions, and emulsions of the active ingredient inaqueous or non-aqueous diluents, syrups, granulates or powders.

E. Formulation and Administration

The composition may, for example, be a food, nutraceutical composition,and/or pharmaceutical composition (medicament). Compositions accordingto the present invention include formulations suitable for oral orparenteral routes. Non-limiting examples of specific routes includeintradermal, subcutaneous, intramuscular, intravenous, local injection,rectal, intranasal inhalation, insufflation, topical (includingtransdermal, buccal and sublingual), vaginal, parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal) and pulmonaryadministration. In non-limiting examples, the formulations canconveniently be presented in food products and/or unit dosage form andcan be prepared by any methods well known in the art. Such methodsinclude the step of bringing into association the active ingredient (forexample, dicholine ellagate) with the carrier which constitutes one ormore accessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith a suitable carrier, such as liquid carriers or finely divided solidcarriers or both, and then if necessary combining with other ingredientsor shaping the product. Formulations of the subject invention suitablefor oral administration can be presented as discrete units such as afood item, capsules, cachets or tablets, each containing a predeterminedamount of the active ingredient, or as an oil-in-water liquid emulsion,water-in-oil liquid emulsion, or as a supplement within an aqueoussolution, for example, a drink such as a tea. The active ingredient canalso be presented as bolus, electuary, or paste. Useful injectablepreparations include sterile suspensions, solutions or emulsions of thecholine salt(s) of an organic compound in aqueous or oily vehicles. Thecompositions can also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection canbe presented in unit dosage form, e.g., in ampoules or in multidosecontainers, and can contain added preservatives. Alternatively, theinjectable formulation can be provided in powder form for reconstitutionwith a suitable vehicle, including but not limited to sterile pyrogenfree water, buffer, dextrose solution, etc., before use. To this end,the choline salt(s) of an organic compound can be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

Formulations suitable for use as a food include, but are not limited todrinks, solid or liquid food items, candies, gums, and/or foodingredients.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth, pastilles that include the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia, mouthwashes that include the active ingredient in a suitableliquid carrier, and chocolate comprising the active ingredients.

Formulations suitable for topical administration according to thesubject invention can be formulated as an ointment, cream, suspension,lotion, powder, solution, paste, gel, spray, aerosol or oil.Alternatively, a formulation can comprise a patch or a dressing such asa bandage or adhesive plaster impregnated with active ingredients, andoptionally one or more excipients or diluents. Topical formulationspreferably comprise compounds that facilitate absorption of the activeingredients through the skin and into the bloodstream.

Formulations suitable for intranasal administration, wherein the carrieris a solid, include a coarse powder having a particle size, for example,in the range of about 20 to about 500 microns, which is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid foradministration by nebulizer, include aqueous or oily solutions of theagent. Formulations preferably can include compounds that facilitateabsorption of the active ingredients through the skin and into thebloodstream.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which can containantioxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which can include suspendingagents and thickening agents, and liposomes or other microparticulatesystems which are designed to target the compound to blood components orone or more organs. The formulations can be presented in unit-dose ormulti-dose or multi-dose sealed containers, such as for example,ampoules and vials, and can be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample, water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions can be prepared from sterilepowders, granules and tablets of the kind previously described.

Liquid preparations for oral administration can take the form of, forexample, elixirs, solutions, syrups or suspensions, or they can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, or fractionated vegetable oils); and preservatives (e.g.,methyl or propyl p hydroxybenzoates or sorbic acid). The preparationscan also contain buffer salts, preservatives, flavoring, coloring andsweetening agents as appropriate.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the choline salt(s) ofan organic compound can be formulated as solutions (for retentionenemas) suppositories or ointments containing conventional suppositorybases such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the choline salt(s) of an organic compound can beconveniently delivered in the form of an aerosol spray from pressurizedpacks or a nebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit canbe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

For prolonged delivery, the choline salt(s) of an organic compoundcontaining composition can be formulated as a depot preparation foradministration by implantation or intramuscular injection. Thecompositions can be formulated with suitable polymeric or hydrophobicmaterials (e.g., as an emulsion in an acceptable oil) or ion exchangeresins, or as sparingly soluble derivatives, e.g., as a sparinglysoluble salt. Alternatively, transdermal delivery systems manufacturedas an adhesive disc or patch, which slowly releases the choline salt(s)of an organic compound for percutaneous absorption, can be used. To thisend, permeation enhancers can be used to facilitate transdermalpenetration of the choline salt(s) of an organic compound. Suitabletransdermal patches are described in for example, U.S. Pat. Nos.5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346;5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475.

Alternatively, other delivery systems can be employed. Liposomes andemulsions are well-known examples of delivery vehicles that can be usedto deliver the choline salt(s) of an organic compound. Certain organicsolvents such as dimethylsulfoxide (DMSO) can also be employed, althoughusually at the cost of greater toxicity.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations useful in the present invention caninclude other agents conventional in the art regarding the type offormulation in question. For example, formulations suitable for oraladministration can include such further agents as food ingredients,sweeteners, thickeners, and flavoring agents. It also is intended thatthe agents, compositions, and methods of this invention be combined withother suitable compositions and therapies.

In one embodiment, the nutraceutical and/or pharmaceutical compositionsof the invention can be administered locally to the area in need oftreatment; such local administration can be achieved, for example, bylocal infusion, by injection, or by means of a catheter. In anotherembodiment, a compound or composition of the invention is administeredin a manner so as to achieve peak concentrations of the active compoundat sites of the disease. Peak concentrations at disease sites can beachieved, for example, by intravenously injecting of the agent,optionally in saline, or orally administering, for example, a tablet,capsule or syrup containing the active ingredient.

F. Other Pharmaceutical and Nutraceutical Agents

Pharmaceutical and nutraceutical formulations of the invention can beadministered simultaneously or sequentially with other drugs orbiologically active agents. Examples include, but are not limited to,antioxidants, free radical scavenging agents, analgesics, anesthetics,anorectals, antihistamines, anti-inflammatory agents includingnon-steroidal anti-inflammatory drugs, antibiotics, antifungals,antivirals, antimicrobials, anti-cancer actives, antineoplastics,biologically active proteins and peptides, enzymes, hemostatics,steroids including hormones and corticosteroids, etc.

G. Therapeutic Methods And Dosage

Preferred unit dosage formulations are those containing a daily dose orunit, daily sub dose, or an appropriate fraction thereof, of an agent.Therapeutic amounts can be empirically determined and will vary with thepathology being treated, the subject being treated, and the efficacy andtoxicity of the agent. Similarly, suitable dosage formulations andmethods of administering the agents can be readily determined by thoseof ordinary skill in the art.

In some embodiments, a therapeutic method of the present invention caninclude treating a disease, condition, or disorder by administering to asubject having such disease or condition a stable formulation asdescribed herein in an amount effective to treat the disease, condition,or disorder. In some embodiments, the subject is administered a stableformulation comprising choline salt(s) of an organic compound. Thedisease, condition, or disorder can be caused by hyperglycemia orobesity. Further, the disease, condition, or disorder can be Type 1diabetes, Type II diabetes, gestational diabetes, latent auto-immunediabetes, prediabetes, or metabolic syndrome and related diseases,conditions, and disorders. For prophylactic administration, thecomposition can be administered to a patient at risk of developing oneof the previously described conditions.

The amount of composition administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, etc. Determination of aneffective dosage is well within the capabilities of those skilled in theart. In some aspects of the invention, total dosage amounts of a cholinesalt of an organic compound will typically be in the range of from about0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may behigher or lower, depending upon, among other factors, the activity ofthe components, its bioavailability, the mode of administration andvarious factors discussed above. Dosage amount and interval can beadjusted individually to provide plasma levels of the compound(s) whichare sufficient to maintain therapeutic or prophylactic effect. Forexample, the compounds can be administered once per week, several timesper week (e.g., every other day), once per day or multiple times perday, depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. Skilled artisans will be able to optimize effective localdosages without undue experimentation. In some embodiments, thecompositions can be administered in conjunction with other compoundknown to effect weight loss. For example, the compounds can be giventogether with compounds known to burn fat.

H. Kits

In another aspect of the present invention, kits for using the methods,producing the choline salt(s) of an organic compound disclosed herein,producing foods, providing foods, or treating a disease, condition ordisorder as described herein. For instance, compositions of the presentinvention can be included in a kit. A kit can include a container.Containers can include a bottle, a metal tube, a laminate tube, aplastic tube, a dispenser, a straw, a pressurized container, a barriercontainer, a package, a compartment, or other types of containers suchas injection or blow-molded plastic containers into which thedispersions or compositions or desired bottles, dispensers, or packagesare retained. The kit and/or container can include indicia on itssurface. The indicia, for example, can be a word, a phrase, anabbreviation, a picture, or a symbol.

In some aspects, the containers can dispense a predetermined amount ofthe composition. In other embodiments, the container can be squeezed(e.g., metal, laminate, or plastic tube) to dispense a desired amount ofthe composition. The composition can be dispensed as a spray, anaerosol, a liquid, a fluid, a semi-solid, or a solid. In a preferredembodiments, the composition is dispensed as a free flowing powder orparticles. The containers can have spray, pump, or squeeze mechanisms. Akit can also include instructions for employing the kit components aswell the use of any other compositions included in the container.Instructions can include an explanation of how to apply, use, andmaintain the compositions. The compositions can, if desired, bepresented in a pack or dispenser device, which can contain one or moreunit dosage forms containing the choline salt(s) of an organic compound.The pack can, for example, comprise metal or plastic foil, such as ablister pack. The pack or dispenser device can be accompanied byinstructions for administration.

EXAMPLES

The present invention will be described in greater detail by way ofspecific examples. The following examples are offered for illustrativepurposes, and are not intended to limit the invention in any mannerThose of skill in the art will readily recognize a variety ofnoncritical parameters which can be changed or modified to yieldessentially the same results.

Example 1

(Method of Making Choline Ellagate Salt(s))

The method below was used to prepare at least one choline ellagate saltof the present invention that can include dicholine ellagate. It isexpected that this method can be used to produce other choline salt(s)of organic compounds by using a different organic compound to contactthe choline. A choline ellagate salt was also produced by the methodbelow using water instead of the 100% methanol where the time for dryingwas increased.

Materials: Ellagic acid dihydrate (EADH, MW 338.2 g/mole), hydroxidesalt of choline (45 wt. % solution in methanol, MW 121.8 g/mole,Sigma-Aldrich®, U.S.A.), methanol (purity 100%), and ethanol (purity100%).

Salt Formation: Ellagic acid dihydrate (10 grams, 0.03 moles) was addedto 100% methanol (35 mL) and stirred to achieve suspension of theellagic acid dihydrate. It is contemplated that the volume of methanolused to suspend the ellagic acid compound can be any amount sufficientto achieve suspension of the ellagic acid compound. The apparent pH ofthis solution was directly tested by pH paper and also tested bydiluting the solution at a 1:10 or 1:20 dilution in distilled water, thepH was found to be 7.0 to 7.6 at room temperature in all instances. Theresultant solution was a cloudy suspension of EADH in methanol.Hydroxide salt of choline (14.92 mL, 0.06 moles, “choline hydroxide”)was added to the EADH suspension under agitation. The resultant solutionwarmed to no more than 50° C. and likely less than 45° C. and the colorof the solution darkened as the EADH dissolved. No heat was added to thesolution. The solution was agitated continually and cooled to 25° C. orbelow to form a choline ellagate salt(s) precipitate. In someexperiments, the solution was cooled to −20° C. to −80° C. The solutionand precipitate was protected from the environment (light, moisture,oxygen) and allowed to equilibrate overnight (8-16 hrs) at a temperatureof 25° C. or below. In some experiments, the solution was cooled to −20°C. to −80° C. After the overnight equilibration, the solution was cooledto −20° C. or below for at least one hour. In experiments, the solutionwas cooled to between −20° C. to −80° C.

Precipitate Salt Processing: The resultant precipitate was collected bygravity filtration through fast flow filter and the filtrate was keptfor flow-through processing. The collected precipitate was washed with10 mL of cold (e.g., −20° C. to −80° C.) 100% ethanol. The ethanol washwas kept for flow-through processing. The washed precipitate was driedunder vacuum with heating at less than 80° C. for 1 hr with stirringevery 10 minutes to break clumps. The precipitate was then further drieduntil the precipitate reached a constant dry weight. The resultantcholine ellagate salt(s) were brown-amber in color and were stored indark amber containers. The approximate yield of the primary cholineellagate salt(s) was 10 grams.

Flow-through Processing: The filtrate and ethanol wash were mixed andthen heated at 100° C. to remove reduce the volume of the solution. When10 mL remained, the solution was cooled to room temperature and filteredto collect the precipitate. The reduced filtrate was retained forfurther flow-through processing. The resultant salt was dried undervacuum with heating at less than 80° C. to a constant dry weight. Theresultant salt was light-amber in color.

The reduced filtrate was then dried under vacuum with heating at lessthan 80° C. to form a precipitate until the precipitate achieved aconstant dry weight. This resultant salt was brown-black in color. Thissalt was saved in a dark amber container.

Example 2

(Characterization of Choline Ellagate Salt(s) of the Present Invention)

The properties of the choline ellagate salt(s) formed by the method ofExample 1 using the methanolic suspension were tested as follows.

Solubility in water was tested at room temperature. The solubility ofthe choline ellagate salt(s) formed by the method of Example 1 is 187mg/mL. As a comparison, ellagic acid has a solubility in PEG 400 at 37°C. of 8 mg/ml and in water of −0.004 mg/mL.

The pH was determined to be 7.0 for a 10 mg/ml solution of the cholineellagate salt(s) in water at room temperature.

A ¹³C NMR spectrum was obtained for the choline ellagate salt(s) formedby the method of Example 1 (See FIG. 1 for the ¹³C NMR spectrum; seeFIG. 2 for the settings). The choline ellagate salt(s) formed by themethod of Example 1 has a similar ¹³C NMR spectrum as reported elsewherefor dicholine ellagate.

It was also surprisingly found that the choline ellagate salt(s) formedby the method of Example 1 possessed less of a amine-type odor (e.g., afish-like odor) than choline ellagate salt(s) made by other methods thatwere tested. Not to be bound by theory, it is believed that the reducedodor may be due to less impurities in the choline ellagate salt(s), suchas amine-type compounds (e.g., trimethylamine, ammonium compounds),and/or the choline of the compound degraded at a reduced rate than thatof all choline ellagate salt(s) made by other methods that were tested.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

1. A method of preparing at least one choline ellagate compound, themethod comprising: (a) obtaining an ellagic acid compound; (b)contacting a choline salt with the ellagic acid compound in a liquid ata pH of 6.95 to 8 and an environment with reduced oxygen to form aliquid suspension containing at least one choline ellagate compound; (c)cooling the liquid suspension of step (b) to 25° C. or below; (d)isolating at least one of the choline ellagate compound(s) from theliquid suspension; and (e) drying the isolated choline ellagatecompound(s).
 2. The method of claim 1, wherein the ellagic acid compoundis ellagic acid dihydrate and/or ellagic acid.
 3. The method of claim 1,wherein step (c) further comprises cooling the liquid suspension in thedark and protected from moisture and oxygen for at least 5 hours.
 4. Themethod of claim 1, wherein the contacting in step (b) increases intemperature to a temperature sufficient to dissolve the ellagic acidcompound and form the at least one choline ellagate compound.
 5. Themethod of claim 1, wherein step (d) isolation further comprises: (i)filtering the liquid suspension to obtain a choline ellagate compound(s)precipitate and a liquid filtrate, wherein the liquid filtrate comprisesadditional dissolved choline ellagate compound(s); and (ii) washing thecholine ellagate compound(s) precipitate with cold ethanol.
 6. Themethod of claim 5, wherein step (d) further comprises: (iii) forming analcoholic solution comprising the liquid filtrate, the ethanolic wash,or both; (iv) isolating additional dissolved choline ellagatecompound(s) from the alcoholic solution; and (v) drying the isolatedcholine ellagate compound(s).
 7. The method of claim 6, wherein step(iv) comprises: (iv.1) reducing the volume of the alcoholic solution;(iv.2) cooling the reduced alcoholic solution to a temperaturesufficient to precipitate the additional dissolved choline ellagatecompound(s) from the solution; (iv.3) isolating the additional cholineellagate compound(s); and (iv.4) drying the isolated choline ellagatecompound(s).
 8. The method of claim 1, wherein the liquid is a solventfor the choline salt and/or the ellagic acid compound.
 9. The method ofclaim 1, wherein the liquid comprises water, methanol, or ethanol, or acombination thereof.
 10. The method of claim 1, wherein the choline saltis a hydroxide salt of choline.
 11. The method of claim 1, wherein thedried isolated choline ellagate compound(s) are substantially devoid offree amine and/or trimethylamine.
 12. The method of claim 1, wherein thedried isolated choline ellagate compound(s) has a low odor or isodorless.
 13. A choline ellagate compound formed by the method ofclaim
 1. 14. A method of preparing a choline salt of an organic compoundcomposition, the method comprising: (a) obtaining an organic compoundcapable of interacting with choline; (b) contacting a choline salt withthe organic compound in a liquid under a reduced oxygen atmosphere and apH of 6.95 to 8 to form a liquid suspension comprising a choline salt ofthe organic compound; (c) cooling the liquid suspension of step (b) to a25° C. to −80° C.; (d) isolating the choline salt of the organiccompound from the liquid suspension; and (e) drying the isolated cholinesalt of the organic compound.
 15. The method of claim 14, wherein theorganic compound is a phytochemical compound.
 16. The method of claim15, wherein the phytochemical compound is a phenolic compound.
 17. Themethod of claim 14, wherein the choline salt is a hydroxide salt ofcholine.
 18. A choline salt of an organic compound formed by the methodof claim 14.